DE2538095A1 - NEW ORGANIC COMPOUNDS, THEIR PRODUCTION AND USE - Google Patents

Description

SAKDOZ-PATENT-GMBH Case 100-4220 '

7850 L ö r r a c h

New organic compounds, their production and uses

The invention relates to compounds of the formula I, in which

X hydrogen or ".ein in 10-. Or 11-position permanent halogen with an atomic weight below 80 "means and

R stands for a radical from the series OR ₁ , SR ₃ , KR ₃ R ₄ , where

R, and R _{2 are} alkyl of 1 to 4 carbon atoms, one

Hydroxyalkyl or aminoalkyl group with 2 to 4 carbon atoms, phenyl or Denote phenylalkyl with 7 to 10 carbon atoms and

R ₃ and R ₄ for hydrogen, alkyl with 1 to 4 carbons

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Substance atoms, phenyl or phenylalkyl with 7 to 10 carbon atoms,

in the form of bases or of acid addition salts.

X denotes in particular hydrogen, fluorine or bromine. if X is fluorine, then it is preferably in the 10 position; X stands for bromine, then it is preferably 11-position. R preferably denotes SR ₃ .

R ₁ or R ₂ represents alkyl having 1 to 4 carbon atoms, co they mean in particular methyl or ethyl, preferably methyl.

If R ₁ or R _{3 are} hydroxyalkyl with 2 to 4 carbon atoms, they are preferably 2-hydroxyethyl. The hydroxyl group is not in the position of the heteroatom to which R ₁ or R _{3 is} bonded.

R. or R ^ stand for aminoalkyl with 2 to 4 carbon atoms, they are preferably 2-aminoethyl. The amino group is not in the α position to the heteroatom to which R. or R is bonded.

If R ₁ or R _{2 are} phenylalkyl with 7 to 10 carbon atoms, they are preferably renzyl or 2-phenyl-thyl.

R. particularly stands for methyl. R ₃ stands in particular for methyl or 2-hydroxyethyl.

If R ₃ or R _{4 are} alkyl having 1 to 4 carbon atoms, they are in particular methyl or ΛοΙ-hyl, preference / ine methyl.

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If R ₃ or R _{4 are} phenylalkyl with 7 to 10 carbon atoms, they are preferably benzyl or 2-phenylethyl.

The compounds are obtained according to the invention of formula I by

a) for the preparation of compounds of the formula Ia in which R ^{1 is} a radical OR or SR ₃ in which R ^ and R _{3 have the} above meaning and X has the above meaning

Compounds of the formula II in which R ¹ has the above meaning, added or added to compounds of the formula III in which X has the above meaning

b) in compounds of the formula IV in which X has the above meaning and Z has one which can be exchanged for R Radical means the radical Z is substituted by the radical R.

Processes a) and b) can be carried out analogously to known methods.

Method a) is an addition reaction. It is carried out under acidic conditions, expediently excluding water. For example, 1.0 to 2.0 moles of acid are used, for example sulfur or Methanesulfonic acid, per mole of compound III.

You can in an inert solvent under the reaction conditions such as chloroform or in a Work excess compound of formula II.

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The reaction temperature can vary, for example from room temperature to 80 ° ; In general, the reaction is expediently carried out at an elevated temperature, for example between 40 ° to 80 °.

Method b) is a nucleophilic substitution reaction, for example by reacting a compound of the formula IV with a compound of the formula V in which M is hydrogen or an alkali metal means and R has the above meaning, can be carried out.

Z in the compounds of the form means]. IV e.g. halogen, e.g. bromine or chlorine. In the compounds of the formula V, M denotes, for example, sodium, lithium, potassium or hydrogen.

The compounds of the formula IV in which Z represents halogen are hydrogen halide addition products of compounds of the formula III. You are unstable. When implementing them with a connection the formula V is expediently worked below -20 °.

The solvent chosen is, for example, an excess of the compound of the formula V used, provided it is liquid at this temperature, or a solvent or suspending agent such as hexane which is still liquid at the reaction temperature and which is inert under the reaction conditions is used.

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The reactions according to process a) or b) result in each case a mixture of compounds of the formula I in which R is in the trans position to the hydrogen atom in the C ₃ position (epivincanol derivatives), and compounds of the formula I in which R in cis- Position to the hydrogen atom is in position C ₃ (vincanol derivatives). Their separation can be carried out analogously to known methods, for example by fractional crystallization or chromatography.

The compounds of the formula I obtainable by the process according to the invention can be present in free form, as a base, or in the form of their addition salts with acids. Acid addition salts, for example hydrogen fumarate, can be prepared from the free bases in a known manner, and vice versa.

The starting products are known or can be prepared by methods known per se.

The compounds of the formula I in free form or in the form of physiologically compatible additive salts ir. with acids (compounds according to the invention) are characterized by interesting pharmaccdynamic Properties. As HeiImIt-'tel be used*

They are useful because they have vigilance-increasing and psychostimulating properties.

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Because of this effect, the inventive Connections e.g. indicated in cerebral vascular damage, in cerebral kerosis, in the case of cerebral insufficiency or loss of consciousness due to head trauma are preferred.

The invention also relates to medicaments which contain a compound of the formula I in free form or in In the form of their physiologically compatible addition-Balze with acids. These remedies for example a solution or a tablet can be made using known methods the usual auxiliary and carrier materials will.

The following examples explain the invention,

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253809S

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HR ¹

II

MR

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III IV

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Example 1 : 14-ϋεοχγ-14 -_ (2-hydroxYäthYl thio) _- yincanol (method a)

13.92 g (50 mmol) (3S, 16S) -Eburnamenin and 4.69 g (60 mmol) of mercaptoethanol were dissolved in 60 ml of 1 M methanesulfonic acid solution in chloroform and Left to stand for 2 hours at 20 °. After partitioning between 50 ml of 2N aqueous ammonia and methylene chloride, drying and evaporation gave a resinous residue. Crystallization from 2-propanol at 0 ° the title compound of m.p. 175 °.

Example 2 :

27.84 g (100 mmol) (3S, 16S) -Eburnamenin were in Dissolve 100 ml of 1 M absolute methanolic sulfuric acid and boil for 30 minutes under nitrogen. After distribution between 200 ml of 2K ammonia and methylene chloride, drying and evaporation obtained amorphous material consisting of a mixture of the two epimeric bases. Fractional crystallization the hydrogen fumarate from 2-propanol at 0 ° first gave crystals of O-methylvincanol hydrogen fumarate, M.p. 161 ° (decomp.), Then crystals of O-methylepivincanol hydrogen fumarate, m.p. 110 ° (decomp.).

The bases were released in each case by distributing between 2N aqueous ammonia and

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ethylene chloride. Crystallization of the obtained oily residues from 2-propanol resulted

O-methylvincanol with a melting point of 106 ° or O-methylepivincanol with a melting point of 163 °.

Example 3 ; 14ΐ2εοχγ-14-methylthio-vincanol (method b)

a) Representation of the hydrogen halide addition pro

For 27.84 g of (3S, 16S) -Eburnamenin is added under Stirring passed at -78 ° absolute hydrogen bromide gas and condensed until at a Volume of 100 ml forms a clear yellow solution.

Always still in the dry ice bath, then at a vacuum of 200 Torr while stirring until it solidifies The pulp is concentrated and the residue is then left without stirring for 16 hours at 20 torr and -78 ° dried. After releasing the vacuum with nitrogen, the brittle residue is at -78 ° powdered.

100 ml of methanethiol are added to the pulverized residue at -78 ° with stirring

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warm up to 0 ° for one hour while stirring and continue stirring at 0 ° for one hour. The reaction mixture is then distributed between 500 ml of 2N ammonia and 200 ml of methylene chloride, the methylene chloride solution is evaporated and the title compound is crystallized from methanol. M.p. 199 °.

Analogously to Example 1, using the appropriate compounds of the formulas. II and III the following compounds of formula Ia

example Compounds of the formula Ia X Snip 4th
5
6th
7th R. H
H
H
F. 95 °
of p-toluenesulfonate
. 167 °
199 °
155 ° SCH (CH ₃ ) ₂
- ^ S (CH ₂ J ₃ CH ₃
---. SCH ₃
·"·· ."NS-

If one proceeds analogously to Example 3, one obtains under Use of the corresponding starting compounds of the formula IV in which Z is Br, the following compounds of formula I.

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r: Q) CNJ ta ro O ΓΝΙ ro ro ro ro ro 3 tn _ ^ O JU ro ^^ ta tH do ta Ö ro CNl U VD ro U Ό U Ϊ2. 3> ta O rH JlJ ro ro to ω Ό υ CNl fO ta CJ . , ^^ ta f. rH ta ΓΝ1 (Nl • η ω CJ ta ta Q) Λ f: ta υ U rj to co Q) O ta ta CO O > do ta Q) ρ ■ Ρ r. u (O β O Q) ro r-1 Q > a O ro υ 3 ο O CV O ο rH f » in r-i VO ί O VD in O O Eh rH rH • 4 ' rH I. Cm H ro O ta, 0 Oa ·· ^H in in r-1 ta C- cn IO -P ο Q) rH Q) rfl Vi ta ta OO ta O Pl ta Ph (M fil CNJ ω CNl ro ro »Υ QJ
• ij O ro ta ro ta r: ro (N ta ro O ta U T ο ta U ta ro U CO Yr CJ CNl O U ro f
I.
I. Ϊα ta t
ι
r CNl ^ - » r) CJ do ta CNl I.
I.
I. U O ta W. CO ^ »» U in -rH t
t
I. t
t ω tH Λ I.
I.
t O H O T r-, Q) fit OO rH cn • Η Q) rH (NJ • rH rH • rH
Q) ω

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Claims (5)

- 12 - 100-4220 Claims ; l / process for the preparation of compounds of the Formula I, wherein X is hydrogen or; sin in the 10th or 11th position 5 permanent ilalogues with an atomic weight below 80 "means and R stands for a residue of the series OR ,, SR ₂ , NE ₃ ^ ₄ , where R ₁ and R _{2 are} alkyl with 1 to 4 carbon atoms, with a 10 hydroxyalkyl or aminoalkyl group 2 to 4 carbon atoms, phenyl or phenylalkyl with 7 to 10 carbon atoms mean and R ₃ and R _{4 represent} hydrogen, alkyl having 1 to 4 carbon atoms, phenyl or phenylalkyl with 7 to 10 carbon atoms, and their acid addition salts, characterized in that that a) for the preparation of compounds of the formula Ia, 2o in which R 'is a radical OR or SR "in where R and R have the above meaning, and X has the above meaning Compounds of the formula II in which R ^{1 has the} above meaning are added to or added to compounds of the formula III in which X has the above meaning 609813/1020 - 13 - 100-4220 b) in compounds of the formula IV in which X has the above meaning and Z has one which can be exchanged for R Radical means the radical Z is substituted by the radical R. and the compounds thus obtained are obtained in free form or in the form of addition salts with acids . 2. The method according to claim 1, characterized in that that one 14-Deöxy-14- (2-hydroxyäthylthio) vincanol manufactures. 3. The method according to claim 1, characterized in that that 14-deoxy-14-methylthio ~ vincanol is produced. 37OO / SM / DK 609813/1020 100-4220 Germany West 4. Compounds of the formula I in which X, R and R, R ", R and R- are those specified in claim 1 Have meaning, in free form or in the form of their addition salts with acids. 5. Medicinal product, characterized in that it contains a compound of the formula I in free form or in the form of a physiologically acceptable addition salt with an acid. SANDOZ - PATENT - QlABE 37OO / SM / DK 609813/1020